title: Genetic-based, differential susceptibility to paraquat neurotoxicity in mice.
abstract: Paraquat (PQ) is an herbicide used extensively in agriculture. This agent is also suspected to be a risk factor for Parkinson's disease (PD) by harming nigro-striatal dopamine neurons. There is likely, genetic-based, individual variability in susceptibility to PQ neurotoxicity related PD. In this study, we measured the delivery of PQ to the brain after three weekly injections of PQ at 5 mg kg(-1), PQ-related neural toxicity after three weekly injections of PQ at 1 mg kg(-1)or 5 mg kg(-1), PQ-related iron accumulation and PQ-related gene expression in midbrain of DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains after a single injection of PQ at 15 mg kg(-1) and 10 mg kg(-1), respectively. Results showed that compared to controls, PQ-treated B6 mice lost greater numbers of dopaminergic neurons in the substantia nigra pars compacta than D2 mice; however, distribution of PQ to the midbrain was equal between the strains. PQ also significantly increased iron concentration in the midbrain of B6 but not D2 mice. Microarray analysis of the ventral midbrain showed greater PQ-induced changes in gene expression in B6 compared to D2 mice. This is the first study to report genetically-based differences in susceptibility to PQ neurotoxicity and to understanding individual differences in vulnerability to PQ neurotoxicity and its relation to PD in humans.
authors.affiliation: Intercollege Graduate Degree Program in Neuroscience, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Yin
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Kavita
authors.initials: K
authors.lastname: Prasad
authors.forename: Eric K
authors.initials: EK
authors.lastname: Richfield
authors.forename: Erica L
authors.initials: EL
authors.lastname: Unger
authors.forename: Jialin
authors.initials: J
authors.lastname: Xu
authors.forename: Byron C
authors.initials: BC
authors.lastname: Jones
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010269:Paraquat / Q000493:pharmacokinetics / Q000633:toxicity*; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D004785:Environmental Pollutants; D007501:Iron; D010269:Paraquat; D004298:Dopamine